This invention relates to 3,4-diphenyl-bicyclo[4.3.0]nonyl derivatives of general formula I 
in which
R1 stands for optionally substituted C1-C20 alkanoyl, optionally substituted C1-C20 alkyl, optionally substituted C7-C20 aralkyl, optionally substituted C7-C15 aroyl, a group PG1 or a hydrogen atom,
R2 stands for optionally substituted C1-C20 alkanoyl, optionally substituted C1-C20 alkyl, optionally substituted C7-C20 aralkyl, optionally substituted C7-C15 aroyl, a group PG2 or a hydrogen atom,
PG1, PG2 are the same or different and stand for a protective group PG,
Axe2x80x2xe2x80x94Axe2x80x94Dxe2x80x94Dxe2x80x2 stands for a xe2x80x94CH2xe2x80x94C(OH)xe2x80x94Cxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Cxe2x80x94C(OH)xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90Cxe2x80x94Cxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x95x90Cxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(OH)xe2x80x94CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x80x94C(OH)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(OH)xe2x80x94C(OH)xe2x80x94CH2xe2x80x94 or 
xe2x80x83group (hydroxy=xcex1 or xcex2; epoxy=xcex1 or xcex2),
X stands for a bond, an oxygen atom, a sulfur atom, SO or SO2,
E stands for a straight-chain or branched-chain alkylene, alkenylene or alkynylene group with up to 15 carbon atoms,
Y stands for halogen (F, Cl, Br, I), for a substituent R4, an optionally substituted aryl or heteroaryl radical, an NR4aR4bxe2x80x94, SO2NR4aR4bxe2x80x94, NR4a(CH2)pxe2x80x94Qxe2x80x94Gxe2x80x94, NR5(CHR6xe2x80x94CHR7)xe2x80x94(CH2)txe2x80x94Qxe2x80x94Gxe2x80x94, SO2NR4a(CH2)pxe2x80x94Qxe2x80x94G, an Oxe2x80x94G, Sxe2x80x94G, SOxe2x80x94G, SOxe2x80x94Gxe2x80x94, SO2xe2x80x94G group,
R4 stands for a hydrogen atom, optionally substituted C1-C20 alkyl, partially or completely fluorinated C1-C20 alkyl, optionally substituted C1-C20 alkanoyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C7-C20 aralkyl, optionally substituted C7-C15 aroyl,
Q stands for an oxygen atom, a sulfur atom, SO or SO2 
G stands for xe2x80x94(CH2)nxe2x80x94R3,
n stands for 0 to 10,
p stands for 1 to 10,
t stands for 0, 1 or 2
R3 stands for hydrogen, a straight-chain or branched-chain alkyl, alkenyl or alkynyl group with up to 10 carbon atoms, a straight-chain or branched-chain, partially or completely fluorinated alkyl or alkenyl group with up to 10 carbon atoms, an optionally substituted C4-C8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted C7-C20 aralkyl group or,
if n greater than 0, also for a hydroxy group or a halogen atom,
R4a, R4b are the same or different in the meaning of R4 or together stand for a C3-C15 alkylene group, which can be straight-chain or branched,
R5 means a hydrogen atom or a C1-5 alkyl group,
R6 and R7 each mean a hydrogen atom, or
R5 and R6 together mean an alkylene group xe2x80x94(CH2)dxe2x80x94 with d=2, 3, 4 or 5 and R7 is a hydrogen atom or
R5 and R7 together mean an alkylene group xe2x80x94(CH2)exe2x80x94 with e=2, 3 or 4 and R6 means a hydrogen atom,
Z stands for hydrogen, halogen, OH, N3, NH2, CO2H, CO2xe2x80x94(C1-C20)-alkyl, C1-C20 alkoxy, xe2x80x94NO2, xe2x80x94CN or C1-C20 acyloxy.
As used throughout this application (e.g., with respect to Y, R4 or R5 groups as defined above), the term heteroaryl means, e.g., a C1-C10 ring which optionally contains one or more (e.g., 1-3) N, S or O atoms in place of C. Also, as used throughout (e.g., with respect to substituents E, R3, R4a or R5 as defined above)i an alkenyene or alkynylene typically contains 1-3 unsaturated bonds.
The invention relates to the diastereomers and/or enantiomers of these derivatives and also their mixtures.
As alkyl groups R1, R2, R3 and R4, straight-chain or branched-chain alkyl groups with up to 20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl.
Alkyl groups R1, R2, R3 and R4 can be fluorinated partially or completely or substituted by 1-10 halogen atoms, hydroxy groups, C1-C4 alkoxy groups, C6-C12 aryl groups, which can be substituted by 1-3 halogen atoms, di-(C1-C4)-alkylamines and tri-(C1-C4)-alkylammonium.
A straight-chain or branched-chain, partially or completely fluorinated alkyl group is preferably the trifluoromethyl or pentafluoroethyl group.
As cycloalkyl groups R3, substituted and unsubstituted radicals with 4 to 8 carbon atoms are considered.
As aryl radicals R3 and R4, substituted and unsubstituted carbocyclic or heterocyclic radicals, such as, e.g., phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, which can be substituted several times by halogen, OH, C1-C20 alkoxy, CO2H, CO2 alkyl, xe2x80x94NO2, xe2x80x94N3, xe2x80x94CN, C1-C20 alkyl, C1-C20 acyl, C1-C20 acyloxy groups and defined groups are suitable. As used throughout this application, acyl can be, e.g., alkanoyl.
The alkanoyl groups that are contained in R1, R2 and R4 of general formula I are to contain 1 to 20 carbon atoms in each case, whereby formyl, acetyl, propionyl and isopropionyl groups are preferred.
The aralkyl groups in R1, R2, R3 and R4 can contain in the ring up to 14 C atoms, preferably 6 to 10 C atoms, and in the alkyl chain 1 to 8, preferably 1 to 4 atoms. As aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are considered. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO2H, CO2 alkyl, xe2x80x94NO2, xe2x80x94N3, xe2x80x94CN, C1-C20 alkyl, C1-C20 acyl, C1-C20 acyloxy groups.
As aroyl radicals for R1, R2 and R4, benzoates and benzoates that are substituted in the phenyl radical are to be preferred.
Free hydroxy groups in l can be modified functionally, for example by etherification or esterification; free hydroxy groups are preferred, however.
As ether, acyl radicals and protective group PG, the radicals that are known to one skilled in the art, such as, e.g., methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl-, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, methyl, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl, isopropionyl, butyryl, pivalyl, and benzoyl radicals are suitable. A survey is found in, e.g., xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Theodora W. Green, John Wiley and Sons).
As specific side chains, in which X stands for an oxygen atom, there can be mentioned
xe2x80x94Oxe2x80x94(CH2)5S(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)5SO2(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)4S(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)4SO(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)4SO2(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)5xe2x80x94Cl
xe2x80x94Oxe2x80x94(CH2)4xe2x80x94Cl
xe2x80x94Oxe2x80x94(CH2)3xe2x80x94Cl
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Cl
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94N(CH3)2 
xe2x80x94Oxe2x80x94(CH2)2-1-Pyrrolidinyl
As side chains in which X stands for a direct bond, for example, the following are considered (DE 1 98 06 357.1)
xe2x80x94(CH2)5N(CH3)(CH2)3C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)6C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)7C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)8C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)6C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)7C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)8C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)2C4F9 
xe2x80x94(CH2)5N(CH3)(CH2)3C6F13 
xe2x80x94(CH2)5N(CH3)(CH2)3C8F17 
xe2x80x94(CH2)5N(CH3)(CH2)6C4F9 
xe2x80x94(CH2)5N(CH3)(CH2)6C6F13 
xe2x80x94(CH2)5N(CH3)(CH2)6C8F17 
xe2x80x94(CH2)5N(CH3)H
xe2x80x94(CH2)5N(H3)(CH2)9H
xe2x80x94(CH2)5-1-Pyrrolidinyl
xe2x80x94(CH2)5N(CH3)(CH2)3OPhenyl
xe2x80x94(CH2)5N(CH3)(CH2)3OBenzyl
xe2x80x94(CH2)5N(CH3)(CH2)3O(CH2)3C2F5 
xe2x80x94(CH2)9S(CH2)3C2F5 
xe2x80x94(CH2)9SO2(CH2)3C2F5 or
xe2x80x94(CH2)9SO2(CH2)3C2F5.
In addition, the side chains of general partial formula 
(WO 98/07740)
can also be considered,
wherein
a is 4, 5 or 6,
b is 0, 1 or 2,
c is 0, 1 or 2,
R5 is a hydrogen atom or a C1-5 alkyl group,
R6 and R7 are each a hydrogen atom, or
R5 and R6 together are an alkylene group xe2x80x94(CH2)dxe2x80x94 with d=2, 3, 4 or 5, and R7 is a hydrogen atom or
R5 and R7 together are an alkylene group xe2x80x94(CH2)exe2x80x94 with e=2, 3 or 4, and R6 is a hydrogen atom, and
U is an unsubstituted ethyl radical or an ethyl radical that is fluorinated in one to five places, or the terminal is substituent xe2x80x94(CH2)3xe2x80x94U in the side chain is replaced by an optionally substituted aryl or heteroaryl radical, which is bonded to the sulfur atom directly or via a mono-, di- or trimethylene group, and of the latter in turn especially the side chains xe2x80x94(CH2)5N(CH3)(CH2)3S(CH2)3C2F5 and xe2x80x94(CH2)5N(R5)(CHR6)CH2S(CH2)3C2F5 with R5+R6=xe2x80x94(CH2)3xe2x80x94.
Specific compounds of general formula I are described in the examples.
In addition to these compounds of general formula I, if a nitrogen atom is contained in Y, this invention also relates to their physiologically compatible addition salts with organic and inorganic acids, these compounds of general formula I including the pharmaceutical preparations that contain addition salts as well as their use for the production of pharmaceutical agents.
For the formation of acid addition salts, inorganic and organic acids are suitable, as they are known to one skilled in the art for the formation of physiologically compatible salts. As addition salts with acids, especially hydrochlorides, hydrobromides, acetates, citrates, oxalates, tartrates and methanesulfonates can be mentioned.
The compounds of general formula I represent compounds with strong antiestrogenic action.
The compounds according to the invention are either pure antiestrogens or so-called partial antagonists, i.e., antiestrogens with partial estrogenic action, such as tamoxifen or raloxifene. In contrast to tamoxifen, in the case of the partial antagonists of general formula I, their agonistic estrogenic action manifests itself in a tissue-selective manner. In particular, the agonistic action manifests itself on bone, in the cardiovascular system and in the CNS (central nervous system). In particular, little or no agonistic action manifests itself in the uterus.
Compounds with antiestrogenic properties, i.e., substances with inhibiting actions compared to estrogens, have already been described extensively.
Antiestrogenically active compounds with a 3,4-diphenyl-bicyclo[4.3.0]nonyl-skeleton that can be compared to the existing compounds do not yet exist, however.
The tamoxifen, (Z)-2-[4-(1,2-diphenyl-1-butenyl)-phenoxy]-N,N-dimethylethylamine that can be seen for the first time from BE 637,389 has been used for breast cancer therapy for longer than antiestrogen.
The steroid derivative 7xcex1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl]-estra-1,3,5(10)-triene-3,17xcex2-diol (EP A 0 138 504, page 58, penultimate compound) that can be seen from EP A 0 138 504 B1 is currently under clinical development for hormone-dependent tumors (breast cancer).
Pharmaceutical compositions that contain sex steroid inhibitors, which are a steroidal skeleton, which has a 7xcex1side chain with the simultaneous presence of at least one other substituent in 14-, 15- or 16-position, are the subject of EP-A 0 376 576.
A considerable number of the most varied compoundsxe2x80x94i.a., those of steroidal origin as well as those with a 2-phenylindole skeletonxe2x80x94which act as antiestrogens and/or which suppress estrogen biosynthesis, are disclosed in WO 93/10741.
Other steroidal antiestrogens, which have an 11xcex2-phenyl radical, are described in EP-AS 0 384 842 and 0 629 635.
The uterus growth test in infant rats, p.o. (test on antiestrogenic action in vivo) confirms the antiestrogenic action of the compounds according to the invention. The test can be performed as described below:
Uterus Growth Test in Infant Rats (Antiestrogenic Action)
Principle of the Method
In rodents, the uterus reacts to the administration of estrogens with an increase of weight (both proliferation and water retention). This growth can be inhibited, depending on the dose, by simultaneous administration of compounds that have an antiestrogenic action.
Execution of the Test
Animals
Infant female rats that weighed 35-45 g at the beginning of the test, 5-6 animals per dose.
Formulation and Administration of Substances
For p.o. administration, the substances are dissolved in 1 part ethanol (E) and made up with 9 parts peanut oil (Exc3x96).
Test Preparation
The young rats just dropped by the mothers are delivered for acclimation one day before the beginning of treatment and immediately supplied with foodxe2x80x94right in the cage.
The treatment is then carried out once daily over 3 days in combination with 0.5 xcexcg of estradiol benzoate (EB). EB is always administered subcutaneously (s.c.), while the test substance is administered p.o. (perorally). 24 hours after the last administration, the animals are weighed, sacrificed, and the uteri are removed. The moist weight (less contents) is determined from the prepared uteri.
Controls
Negative control: vehicle (E/Exc3x96), 0.2 ml/animal/day
Positive control: 0.5 xcexcg of EB/0.1 ml/animal/day
Evaluation
Of the relative organ weights (mg/100 g of body weight), the average values with standard deviation (X+SD) and the significance of the differences to the control group (EB) in the Dunnett test (p less than 0.05) are determined for each group. The calculation of inhibition (in %) compared to the ED control is carried out with a program. The relative levels of effectiveness of the test substances are determined by a co-variance and regression analysis.
The compounds according to the invention, especially if they are pure antiestrogens, are suitable for the therapy of estrogen-dependent diseases, such as, for example, breast cancer (second-line therapy of tamoxifen-resistant breast cancer; for adjuvant treatment of breast cancer instead of tamoxifen), endometrial carcinoma, prostate cancer, prostate hyperplasia, anovulatory infertility and melanoma.
In addition, the pure antiestrogens of general formula I can be used as components in the products that are described in EP 346 014 B1, which contain an estrogen and a pure antiestrogen, specifically for simultaneous, sequential or separate use for the selective estrogen therapy of peri- or post-menopausal women.
The compounds of general formula I, especially if these are pure antiestrogens, can be used together with antigestagens (competitive progesterone antagonists) for the treatment of hormone-dependent tumors (EP 310 542 A).
Other indications, in which the compounds of the general formula can be used, is male hair loss, diffuse alopecia, an alopecia that is caused by chemotherapy, as well as hirsutism (Hye-Sun Oh and Robert C. Smart, Proc. Natl. Acad. Sci. USA, 93 (1996) 12525-12530).
In addition, the compounds of general formula I can be used for the production of medications for treating endometriosis and endometrial carcinomas.
The compounds of general formula I can also be used for the production of pharmaceutical compositions for male and female birth control (male birth control: DE-A 195 10 862.0).
The compounds of general formula I with tissue-selective partial estrogenic action can be used primarily for prophylaxis and therapy of osteoporosis and for the production of preparations for substitution therapy in pre-, peri- and post-menopause (HRT=hormone replacement therapy) (Black, L. J.; Sato, M.; Rowley, E. R.; Magee, D. E.; Bekele, A.; William, D. C.; Cullinan, G. J.; Bendele, R.; Kauffman, R. F.; Bensch, W. R.; Frolik, C. A.; Termine, J. D. and Bryant, H. U.: Raloxifene [LY 139481 HCl] Prevents Bone Loss and Reduces Serum Cholesterol without Causing Uterine Hypertrophy in Ovariectomized Rats; J. Clin. Invest. 93: 63-69, 1994).
The invention also relates to pharmaceutical preparations that contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids thereof) and the use of these compounds for the production of pharmaceutical agents, especially for treating estrogen-dependent diseases and tumors and pharmaceutical agents for hormone replacement therapy (HRT).
The compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredients one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants and other commonly used vehicles and diluents can be used.
As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmans Encyklopxc3xa4die der technischen Chemie [Ullmans"" Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 and ff.; issued by Czetsch-Lindenwald. Hilfsstoffe fxc3xcr Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]: Pharm. Ind. Issue 2, 1961, page 72 and ff.; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fxc3xcr Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields] Cantor K G, Aulendorf in Wxc3xcrttemberg 1971.
The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue. The amount of the compounds that is to be administered varies within a wide range and can cover any effective amount. On the basis of the condition that is to be treated and the type of administration, the amount of the administered compound is 0.1-25 mg/kg of body weight, preferably 0.5-5 mg/kg of body weight, per day. In humans, this corresponds to a daily dose of 5 to 1250 mg.
The preferred daily dosage in humans is 50 to 200 mg. This holds true especially for tumor therapy.
For oral administration, capsules, pills, tablets, coated tablets, etc., are suitable. In addition to the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc. The individual dosage units for oral administration can contain, for example, 5 to 500 mg of the active ingredient.
To achieve better bio-availability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with xcex1-, xcex2- or xcex3-cyclodextrin or derivatives thereof (PCT/EP95/02656).
According to the invention, the compounds of general formula I can also be encapsulated with liposomes.
For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluents, very often oils with or without the addition of a solubilizer, a surfactant, a suspending agent or an emulsifier are used. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
The compounds of general formula I can also be formulated in the form of a solution that is intended for oral administration, and that in addition to the active compound of general formula I contains
a) a pharmaceutically compatible oil and/or
b) a pharmaceutically compatible lipophilic surfactant and/or
c) a pharmaceutically compatible hydrophilic surfactant and/or
d) a pharmaceutically compatible water-miscible solvent.
In addition, reference is made to WO 97/21440 in this respect.
The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated in such a way that a delayed release of active ingredient is made possible.
As inert materials, implants can contain, for example, biodegradable polymers or synthetic silicones, such as, for example, silicone gum. In addition, the active ingredients can be embedded in, for example, a patch, for percutaneous administration.
For the production of intravaginal systems (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, coils) that are loaded with active compounds of general formula I, various polymers are suitable, such as, for example, silicon polymers, ethylene vinyl acetate, polyethylene or polypropylene.
The compounds according to the invention can be used alone or to achieve additive or synergistic actions in combination with other principles and classes of substances that can be used in tumor therapy.
As examples, there can be mentioned the combination with
Platinum complexes, such as, e.g., cis-platinum, carboplatinum,
intercalating substances, e.g., from the class of anthracyclines, such as, e.g., doxorubicin or from the class of anthrapyrazoles, such as, e.g., Cl-941,
substances that interact with tubulin, e.g., from the class of vinca-alkaloids, such as, e.g., vincristine, vinblastine or from the class of taxanes, such as, e.g., taxol, taxotere or from the class of macrolides, such as, e.g., rhizoxin and its analogs, epothilone B and its analogs, discodermolide and its analogs, eleutherobine and its analogs, or other compounds, such as, e.g., colchicine, combretastatin A-4,
DNA topoisomerase inhibitors, such as, e.g., camptothecin, etoposide, topotecan, teniposide,
folate- or pyrimidine-antimetabolites, such as, e.g, lometrexol, gemcitubin,
DNA-alkylating compounds, such as, e.g., adozelesin, dystamycin A,
inhibitors of growth factors (e.g., of PDGF, EGF, TGFxcex2, EGF), such as, e.g., somatostatin, suramin, bombesin antagonists,
inhibitors of protein tyrosine kinases or protein kinases A or C, such as, e.g., erbstatin, genistein, staurosporine, ilmofosine, 8-Cl-cAMP,
antihormones from the class of antigestagens, such as, e.g., mifepristone, onapristone or from the class of antiestrogens, such as, e.g., tamoxifen or from the class of antiandrogens, such as, e.g., cyproterone acetate (combination with antigestagens, see, for example, EP 0 310 542 B1 and EP 0 310 541 B1),
metastases-inhibiting compounds, e.g., from the class of eicosanoids, such as, e.g., PGl2, PGE1, 6-oxo-PGE1 as well as their more stable derivatives (e.g., iloprost, cicaprost),
inhibitors of oncogenic RAS proteins, which influence the mitotic signal transduction, such as, for example, inhibitors of the farnesyl-protein-transferase,
natural or synthetically produced antibodies, which are directed against factors or their receptors, which promote tumor growth, such as, for example, the erbB2 antibody.
The invention also relates to a process for the production of compounds of formula I, which are described in more detail in Diagram 1 below. 
Step a (IIIII)
Ketone II, in which PG1H can have the meanings that are mentioned above for PG1 or PG1H means a hydrogen atom, is produced according to processes that are known in the literature. The reaction to an aryl compound of formula III is carried out by reaction with an organometallic compound of general formula 
in which M stands for an alkali metal or for a divalent metal atom M-Hal, in which Hal is a halogen atom, PG2H has the meanings that are mentioned above for PG2 and Z or PG2H means a hydrogen atom, and free OH, CO2H or NH2 groups in Z are optionally protected. As divalent metal, magnesium and zinc are preferred; as halogen, Hal is preferably chlorine, bromine and iodine. The reaction is carried out in an inert solvent, preferably in tetrahydrofuran or diethyl ether. As PG1H, hydrogen or a protective group PG1 in the meaning of tert-butyl- or tert-butyldimethylsilyl is preferred; as PG2H, hydrogen or a protective group PG2 in the meaning of methyl, benzyl, or tert-butyldimethylsilyl is preferred. A selective modification of protective groups PG1 and/or pG2 is possible.
Step b (IIIIV)
The elimination of water in III to olefin IV is carried out according to the methods that are known to one skilled in the art. The use of mineral aqueous acids and inert organic, water-miscible solvents, such as, for example, dioxane or tetrahydrofuran, is preferred. Under these conditions, protective groups PG1 and/or PG2 that can be cleaved acidically are also eliminated. A selective modification of protective groups PG1 and/or PG2 is possible. As PG1H, hydrogen or a protective group PG1 in the meaning of tert-butyl- or tert-butyldimethylsilyl is preferred; as PG2H, hydrogen or a protective group PG2 in the meaning of benzyl- or tert-butyldimethylsilyl is preferred.
Step c (IVV)
Water is added to the double bond in IV in an anti-Markovnikov orientation. For this purpose, the processes that are known to one skilled in the art are suitable, such as, e.g., reaction with boranes, their subsequent oxidation to the corresponding boric acid esters and their saponification. As boranes, e.g., the borane-tetrahydrofuran complex, the borane-dimethyl sulfide complex, 9-borabicyclo[3.3.1]nonane in an inert solvent such as, for example, tetrahydrofuran or diethyl ether, are preferred. As oxidizing agents, preferably hydrogen peroxide is used; for saponification of the boron esters, preferably alkali hydroxides, such as, e.g., sodium hydroxide, are used.
Step d (VVI)
The oxidation of the alcohol in V to ketone is carried out according to the methods that are known to one skilled in the art. For example, oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation according to Swern or related methods, e.g., with use of oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martin periodinane, the use of nitrogen oxides, such as, e.g., N-methyl-morpholino-N-oxide in the presence of suitable catalysts, such as, e.g., tetrapropylammonium perruthenate in inert solvents, can be mentioned. Preferred is the oxidation with the chromium-trioxide-pyridine complex. A selective modification of protective groups PG1 and/or PG2 is possible. As PG1H, hydrogen or a protective group PG1 in the meaning of tetrahydropyranyl or tert-butyldimethylsilyl is preferred; as PG2H, hydrogen or a protective group PG2 in the meaning of tetrahydropyranyl, benzyl or tert-butyldimethylsilyl is preferred.
Step e (VIVII)
The reaction of ketone VI to an aryl compound of formula VII is carried out by reaction with an organometallic compound of general formula 
in which M stands for an alkali metal or for a divalent metal atom M-Hal, in which Hal is a halogen atom, and Y, E and X have the above-mentioned meanings; free OH, SH or NH groups are optionally protected in Y; Xxe2x80x2 stands for a protected hydroxy group OPG, and Yxe2x80x2 stands for a group OLG, a halogen atom (F, Cl, Br, I) or a group OPG. As a divalent metal, magnesium and zinc are preferred; as halogen, Hal is preferably chlorine, bromine and iodine. The reaction is carried out in an inert solvent, preferably in tetrahydrofuran or diethyl ether. A selective modification of Y as well as of protective groups PG1 and/or PG2 is possible. As PG1H, hydrogen or a protective group PG1 in the meaning of acetyl, tetrahydropyranyl or tert-butyldimethylsilyl, is preferred; as PG2H, hydrogen or a protective group PG2 in the meaning of tetrahydropyranyl, benzyl or tert-butyldimethylsilyl is preferred.
Hydroxyl groups that are released into Xxe2x80x2 or Yxe2x80x2 can be modified further by etherification.
If Yxe2x80x2 represents a halogen, preferably Cl, Br, I or a leaving group OLG, the additional chain creation can be carried out by, for example, alkylation, amination (e.g., with HNR4aR4b, HNR4a(CH2)pxe2x80x94Qxe2x80x94G) or etherification (e.g., with HOxe2x80x94G, HSxe2x80x94G).
To create the side chain, reference is otherwise made to the processes and examples that are described in EP A 0 138 504, EP-A 0 376 576, WO 98/07740 and DE 1 98 06 357.1 for the creation of the 7xcex1-side chain of the steroid. By an analogous procedure, the side chains that are described there and synthesized can be created in these compounds as xe2x80x94Xxe2x80x94Exe2x80x94Y.
Step f (VIVIII)
The reaction of ketone VI to an enol compound of formula VIII, in which LG represents a leaving group, is carried out according to the processes that are known to one skilled in the art. By using a strong base in an inert solvent, such as, for example, tetrahydrofuran or diethyl ether, the enolate of ketone VI is generated and then reacted with a compound LG-Hal, in which Hal has the meaning of fluorine, chlorine, bromine or iodine. As leaving group LG, for example, alkylsulfonyls or optionally substituted arylsulfonyls, for example the tosylate radical, are suitable; preferred are perfluorinated alkylsulfonyls, such as, for example, perfluorobutylsulfonyl or trifluoromethylsulfonyl. As PG1H, a protective group PG1 in the meaning of tetrahydropyranyl or tert-butyldimethylsilyl is preferred; as PG2H, a protective group PG2 in the meaning of tetrahydropyranyl, benzyl or tert-butyldimethylsilyl is preferred.
Step g (VIIIxe2x80x2)
The elimination of water in VII to compounds of formula Ixe2x80x2 with Axe2x80x94D in the meaning of a Cxe2x80x94C double bond is carried out according to the conditions that are mentioned under step b. The double bond can optionally be hydrogenated (Axe2x80x94D in the meaning of a Cxe2x80x94C-single bond) or oxidized (Axe2x80x94D in the meaning of a 
a COHxe2x80x94CHxe2x80x94, a CHxe2x80x94COHxe2x80x94 or a COHxe2x80x94COH group) according to the processes that are known to one skilled in the art. A selective modification of Y as well as of protective groups PG1 and/or PG2 is possible. As PG1H, hydrogen or a protective group PG1 in the meaning of acetyl, tetrahydropyranyl or tert-butyldimethylsilyl is preferred; as PG2H, hydrogen or a protective group pG2 in the meaning of tetrahydropyranyl, benzyl or tert-butyldimethylsilyl is preferred.
Step h (VIIIIxe2x80x2)
The reaction of compound VIII is carried out according to the methods that are known to one skilled in the art. It is preferably reacted with a boronic acid of formula 
in which Y, E, X, Yxe2x80x2 and Xxe2x80x2 have the above-mentioned meanings, and free OHxe2x80x94, SHxe2x80x94 or NH groups are optionally protected in Y, under palladium(O)-catalysis to a compound of formula Ixe2x80x2 with Axe2x80x94D in the meaning of a Cxe2x80x94C double bond. The double bond can optionally be hydrogenated (Axe2x80x94D in the meaning of a Cxe2x80x94C single bond) or oxidized (Axe2x80x94D in the meaning of a 
a COHxe2x80x94CHxe2x80x94, a CHxe2x80x94COHxe2x80x94 or a COHxe2x80x94COH group) according to the processes that are known to one skilled in the art. A selective modification of Y as well as of protective groups PG1 and/or PG2 is possible. As PG1H, hydrogen or a protective group PG1 in the meaning of acetyl, tetrahydropyranyl or tert-butyldimethylsilyl is preferred; as PG2H, hydrogen or a protective group PG2 in the meaning of tetrahydropyranyl, benzyl or tert-butyldimethylsilyl is preferred. The cleavage of protective groups that are optionally contained in Ixe2x80x2 according to the processes that are known to one skilled in the art results in compounds, I according to the invention.
The compounds according to the invention can be produced as described below. By an analogous procedure using analogous reagents in the data that is contained in the examples, additional compounds of general formula I can be obtained.
As processes for the creation of side chain xe2x80x94Xxe2x80x94Exe2x80x94Y in the compounds according to the invention, especially also methods of side chain introduction and of side chain creation that are described in EP 0 138 504 B1 and EP 0 376 576 A are suitable.
A thio bridge in the side chain can be oxidized with sodium periodate to sulfoxide; the sulfoxides and sulfones are obtained from the sulfides with a peracid as an oxidizing agent, e.g., m-chloroperbenzoic acid.
The saponification of ester groupings as well as esterification and etherification of free hydroxy groups is carried out in each case according to established processes of organic chemistry.
The acid addition salts of the compounds of general formula I can also be produced according to standard processes from the compounds of general formula I.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and publications, cited above and below, and of corresponding German application No. 198 26 213.2, filed Jun. 9, 1998 is hereby incorporated by reference.